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THE CLINICAL FEATURES AND TREATMENT METHODOLOGIES OF GOUT

Sikander Ali, Manahil Ghazi, Syeda Manam Rubab Zahra

Institute of Industrial Biotechnology Government College University, Lahore, Pakistan.

Article Received on 12/04/2017 Article Revised on 03/05/2017 Article Accepted on 24/05/2017

INTRODUCTION

Gout is a form of arthritis, affecting the bones and joints.

It is a metabolic syndrome and itself related to a set of

disorders. The main cause of gout is known to be the

accumulation of uric acid due to its improper breakdown.

Hence the condition is also characterized as

hyperuricemia. Gout can affect any one. Men are most

likely to be affected by gout. Gout can also affect women

especially after menopause. This excess of uric acid

causes attacks of sudden pain in the joints. It is very

painful and the affected area might get permanently

disabled afterwards. Accompanied by hyperuricemia, the

gout develops as the uric acid soluble concentration in

the body fluids exceeds i.e., almost as higher as 400ug

per liter of the blood. This high concentration of uric acid

begins to form crystals which further aggravate the

condition. Sometimes this deposition of crystals is silent

and painless which is referred to as gouty tophus.[1]

Figure 1: Characterized Stages of Gout

SJIF Impact Factor 4.161

ReviewArticle

ISSN 2394-3211

EJPMR

EUROPEAN JOURNAL OF PHARMACEUTICAL

AND MEDICAL RESEARCH www.ejpmr.com

ejpmr, 2017,4(6), 202-211

*Corresponding Author: Sikander Ali

Institute of Industrial Biotechnology Government College University, Lahore, Pakistan.

ABSTRACT

Gout is the most prevalent inflammatory arthritis and affects 2.5% of the general population in the UK. It

is characterized by recurrent attacks of a red, tender, hot, and swollen joint. Pain typically comes on rapidly in less

than twelve hours. The joint at the base of the big toe is affected in about half of cases. It may also result

in tophi, kidney stones, or urate nephropathy. It is the only arthritis that has the potential to be cured with safe,

inexpensive and well tolerated urate-lowering treatments, which reduce serum uric acid by either inhibiting

xanthine oxidase – e.g. allopurinol or by increasing the renal excretion of uric acid. Of these, xanthine oxidase

inhibitors are used first line and are effective in curing gout in the majority of patients. Gout can be diagnosed on

clinical grounds in those with typical podagra. However, in those with involvement of other joints, joint aspiration

is recommended to demonstrate monosodium urate crystals and exclude other causes of acute arthritis, such as

septic arthritis. However, a clinical diagnosis of gout can be made if joint aspiration is not feasible. Gout was

historically known as "the disease of kings" or "rich man's disease". It has been recognized at least since the time of

the ancient Egyptians.

KEYWORDS: Tophi, Urate nephropathy, Xanthine oxidase, Allopurinol, Septic arthritis, MRI, CT, DECT.

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It was Garrod who almost 150 years ago identified that

uric acid is elevated in the blood of gout patients, a

condition that can be referred as hyperuricemia. This

deposition of uric acid can occur in other tissues as well,

not necessarily the joints. Hence it is also a leading cause

for tophi, nephropathy, and kidney stones. The condition

has its various stages of attack; however, the separation

between the stages may be incomplete. In some cases,

stage 1 can reflect the complete disease. Uric acid

concentration of blood serum may continue to rise but is

symptomless and would be referred to as its first

developing stage. Then the second stage, acute gouty

arthritis develops. Almost 40 to 60 percent of the acute

gout may develop chronic gout within a year and its

conditions worsen. However, if left untreated, further

complications are observed.[2]

Figure 1 shows some of

the characterized stages of gout.

SYMPTOMS

Excess of uric acid causes attacks of sudden pain in the

joints. The joints are more likely to be swelled, redden

and become stiff making it difficult to move the affected

joint. The big toe is most likely to be affected by the gout

i.e., the joint at the base of the toe. The attacks of pain

can occur several times in a particular period until the

disorder is treated completely. Prolonged gout continues

to affect the joints, tendons that attach these joints to

muscles and also nearby tissues. The pain originates

mostly in the midnight and seems to be unbearable when

given any stress or weight on it. The attack of such pain

can prolong from a few days until many weeks. However,

the next attack may not occur for even several months or

years. Even though no painful sensation is felt, the buildup

of urate crystals keeps on damaging the joints.[3]

The joint

may deform in shape (Fig. 2).

Figure 2: Vulnerable joints to be affected by Gout

The most commonly observed signs and symptoms of

gout occurring mostly at night include intense joint pain

in the big toe usually, but can also occur feet, ankles,

knees, hands and wrists which is very much intense in

the first 4 to 12 hours. Lingering discomfort which is the

after-pain, occurring after the major pain subsides.

Sometimes the joint pain continues for days or weeks.

These later attacks prolong for even larger durations and

thus affecting more joints. Other symptoms include

inflammation and redness in the affected joint which

definitely become swollen red and is also hotter than the

nearby tissues or cells. Also there remains only a limited

range of motion in the affected part. As the gout

progresses, the effected joints lessen in their ability of

making appropriate movements.[4]

CAUSES

Excess of uric acid can cause gout. Excess of uric acid is

not always harmful, many of the people having higher

level of uric acid does not develop gout, but when level

of uric acid gets high in blood they form crystals in

joints which cause inflammation and severe kind of

pain. Normally much of the uric acid is excreted through

urine. Uric acid dissolves in the blood, carried to kidney

and then removed but urate crystals form when this

normal path way is disturbed. This happens when either

the body began to produce too much uric acid or the

kidneys fail to excrete this excessive uric acid. The result

is the formation of its crystals (urate crystals) which

deposit into the joints.[5]

Figure3. Further complications in the Gout condition

Chances of gout are higher on people who are

overweight. The chances increase more if the meal of

such people includes fish or meat, sea food and steaks.

This is because of the fact that fish and meat contains

chemicals that ultimately forms purines in the body after

their intake. Actually purines after their breakdown lead

to the formation of uric acid. However, a moderate

consumption of purine containing diet doesn’t cause

gout. Also the risk is higher in people who drink too

much alcohol, beer, wine and fructose containing drinks.

After alcohol consumption, there is a great breakdown of

ATP and lactic acid which increases the uric acid load

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and minimizes its elimination from the body. Fructose is

the only sugar that increases the uric acid load because it

also enhances the ATP breakdown like alcohol. Not only

this, it develops insulin resistance thus reducing the

amount of uric acid excretion by kidneys.

Medicines like diuretics can cause gout too.

Hypertension can also cause gout. A patient of gout has

more chances of getting a heart attack or heart failure.[6]

Figure 3 explain the complications caused by gout.

Risk factors

The causative factors for gout are quite numerous. Diet is

one of them. The chances increase more if the meal of

such people includes fish or meat, sea food, steaks. This

is because of the fact that fish and meat contains

chemicals that ultimately forms purines in the body after

their intake. Actually purines after their breakdown lead

to the formation of uric acid.[7]

Also the risk is higher in

people who drink too much alcohol, beer, and fructose

containing drinks. Chances of gout is higher on people

who are over-weight because if one is obese the body

produces much uric acid which in turn is difficult for the

kidney to eliminate and chances of getting gout are

greater[8]

. Figure 4 shows relative incidents of gout

caused by alcohol intake.

Fig 4: Relative incidents of gout caused by alcoholic beverages

Some conditions and diseases enhance the risk for gout.

These include untreated high blood pressure, diabetes,

metabolic syndrome, heart diseases, and kidney diseases.

Family history of gout can also be an important risk

factor. If the ancestors of the family have had gout the

chances of having gout are greater in the progeny.[8]

Another factor includes the age and sex of an

individual. Chances of having gout are more in men as

compared to women due to menstruation but after

menopause the level become same as men. Gout is

common in men in age of 30-50 year whereas women

develop the symptoms after menopause. The factors of

minor importance include recent surgical operation such

as surgery or trauma is also linked with greater risk of

having gout.[9][10]

Also the socioeconomic conditions of a

country also determine the particular risk of developing

gout for that country.[11]

Table 1shows risk factors and

frequency of gout.

Table 1: Risk factors of Gout and their relative risks

RISK FACTOR NOTES RELATIVE RISK

Diuretic use — 3.37 (2.75 to 4.12)

Alcohol intake ≥ 50 g per day vs. none 2.53 (1.73 to 3.70)

Beer ≥ 2 drinks per day vs. none 2.51 (1.77 to 3.55)

Spirits ≥ 2 drinks per day vs. none 1.60 (1.19 to 2.16)

Wine ≥ 2 drinks per day vs. none 1.05 (0.64 to 1.72)

Hypertension — 2.31 (1.96 to 2.72)

EPIDEMIOLOGY

There has ban a significant difference between the

epidemiology of gout within different countries because

of the differences in their methodologies, lifestyle and

diet etc. This distribution of gout is very uneven across

the countries. The risk is affected by seasons, age, and

sex and also by the race of the individual. The seasons

also can determine the risk of developing gout; some

studies state that in spring season, the risk is higher. This

can be because of the changes in the diet, temperature

and physical wok activity of the individuals which is

affected by the particular season.[12]

Globally, the gout

burden has increased a lot over the past 50 years. Gout is

prevalent more in males than females. Males over the

age of 30 are most vulnerable however, for females age

is extended up to 50 years after which they become more

vulnerable to gout after menopause because of the

decreased effect of hormones like oestrogen,

progesterone etc.[13]

The rate of being affected by gout in

both the males above 30 years and females above 50

years is approximately 2 percent (Fig 5).

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Table 2: Incidence and Prevalence of Gout in Respective years

SOURCE YEAR PREVALENCE INCIDENCE

National health and nutrition survey

(NHANES III)

1988 to

1994 5.1 million NR

US manage care

claims Database

1990

1999

2.9 to 5.2 /100,000

persons NR

Rochester

Epidemiology

Project

1977 to 1976

1995 to 1996 NR

45 to 62.3/ 100,000

persons

National health interview survey 1992

1996 2 million

>46% in men

>2% in women

Gout is very much prevalent in the people of Pacific

region which include Canada, china, japan, Australia,

chile, combodia, Singapore, South Korea and others.

Australian men have high serum uric acid concentration.

Sub-Sahara Africa and Polynesia are also affected

adversely.[14]

However, surprisingly, developed countries

have more incidence and risk of gout disorder as

compared to the developing countries.[14]

In the west,

about 1 to 2 per cent of the population gets affected by

gout. The disease is becoming more common there day

by day. In 2013, at least 5.8 million people were gout

patients around all the western countries. Overall rate of

gout in western countries increased to double during

1990 to 2010 due to increasing high blood pressure in the

population, changes in the diet, efforts to increase life

expectancy etc. The African migrants of America have

twice the risk of gout than the European migrants.[15]

(Table 2).

Figure 5: Comparative increasing risk of gout with age in men and woman

PATHOGENESIS AND PATHOPHYSIOLOGY

Gout is actually because of the improper metabolism of

purine, whose breakdown product uric acid begins to

accumulate as the crystals. Uric acid picks up the sodium

ions and form monosodium urate crystals in joints or

tendons and in the nearby tissues. If the crystals are

small, a set of proteins totally surround it and avoid its

contact with the nearby cells, thus no inflammation is

produced.[16]

Continuous an Gout is a disorder of purine

metabolism and occurs when its final metabolite, uric

acid, crystallizes in the form of monosodium

urate, precipitating and forming deposits (tophi) in joints,

on tendons and in the surrounding tissues. Microscopic

tophi may be walled off by a ring of proteins, which

blocks interaction of the crystals with cells and therefore

avoids inflammation. Naked crystals may break out of

walled-off tophi due to minor physical damage to the

joint, medical or surgical stress, or rapid changes in uric

acid levels. When they break through the tophi, they

trigger a local immune-mediated inflammatory reaction

in macrophages, which is initiated by the NLRP3 in

flammasome protein complex. Activation of the NLRP3

in flammasome recruits the enzyme caspase 1, which

converts pro-interleukin 1β into active interleukin 1β,

one of the key proteins in the inflammatory cascade.[17]

(Fig 6).

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Figure 6: Pathways responsible For Uric acid production in body

Out of the two main factors which include over

production by the body and under excretion by the

kidneys, the under excretion comprises of 70 percent of

the uric acid load. Various transporters of uric acid have

been known in the kidney tubules and intestinal tract

showing the pathway and accumulation of excessive uric

acid- hence showing the pathogenesis pathway of gout.

The uric acid might exist in the form of monosodium

urate crystals in the kidneys. Increase of monosodium

urate crystals increases the risk of gout. However, all

hyperuricemic patients might not develop gout at all.

Normally the 30 percent of the purines come from the

diet and the rest 70 percent is synthesized by the body

itself through the nucleotides synthesis and metabolism

etc. The fate of purines is its breakdown to uric acid

ultimately.[18]

Figure 7: Defective uric acid metabolism in gout patients (the uricase enzyme doesn’t act on uric acid and it

begins to accumulate as crystals in the joints etc.)

Under normal conditions the uric acid is excreted

directly through kidneys and through the gut or either it

breaks down allatoin and then to urea and then to

ammonia finally. However, in gout the enzyme uricase is

defective or non- functional or partly functional hence

the uric acid began to accumulate in the body in the form

of crystals and deposits in joints and tissues etc. The

monosodium crystals deposits of the uric acid induce the

inflammation response by activating certain components

of immune system. The macrophages try to phagocytosis

the crystals by activating NALP-3 inflammasome, which

in turn directs inflammation. The white blood cells

proliferates and antibodies are released which generates

an intense response of pain. White blood cells release

phagocytizing lysozymes for these monosodium crystals.

Complement protein pathways and toll like receptors are

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also activated to perform their work against the

crystals.[19]

(Fig 7).

TYPES OF GOUT ON THE BASIS OF DIFFERENT

FEATURES

Acute gout

Acute gout attacks are characterized by typical features

of acute crystal synovitis, such as rapid onset (symptoms

peaking within 12–24 hours of onset), excruciating joint

pain, exquisite tenderness to touch, erythema and

articular/periarticular swelling. The attack usually

resolves in 1–2 weeks.[20]

In acute gout, there is an

inflammation of synovial membrane with severe joint

pain, sensitive to touch, erythema and joint swelling.

Metatarsophalangeal joint is most affected. In addition

ankle, mid foot, wrist, knees and elbows can also be

affected. Onset of acute gout occurs in lower limb and

then poly-articular regions are affected. It may be caused

by an injury, excess alcohol intake or may be due to

dehydration.[21]

(Fig.8 i).

Chronic tophaceous gout

It involves chronic joint pain, increase in sensitivity and

stiffness of joints with attacks of acute gout. It occurs

after many year attacks of acute gout. It involves

formation of nodules having MSU crystals which

appears as white colour to yellow firm subcutaneous

masses usually in feet and finger tips, also found in the

olecranon and pre-patellar bursae.[22][23]

(Fig 8 ii)

Transplant-associated gout

It can develop within three to five years in transplant

recipients. It occurs in patients having

immunosuppressed solid organ transplant and receive

very low dose of steroid prednisolone as well as low

dose of calcineurin inhibitors e.g. cyclosporine.[23]

Figure 8: i. acute gout ii. Chronic gout

Comorbidities

The patients of gout have several other disorders like

hypertension, obesity, ischemic heart disease and

congestive cardiac failure as well as insulin resistance,

hyperlipidemia and renal impairment are very common.

The presence of these diseases must be properly

treated.[23]

(Table 3).

Table 3: Comorbidities associated with Gout

COMORBIDITIES

Over weight / Obesity >71

Insulin resistance syndrome 63%

Type II diabetes 15%

Renal insufficiency 5%

Kidney stones 14-15 %

INVESTIGATION AND DIAGNOSIS

USING BODY FLUIDS: Gout is diagnosed by

polarized light microscopy of peripheral blood, synovial

fluid and by urinary uric acid excretion.[24]

Peripheral blood

Peripheral blood can be used for the diagnosis of gout. In

case of acute gout, the concentration of neutrophils and

other inflammatory markers is very high. So by seeing its

concentration, acute gout can be diagnosed. Similarly the

concentration of SUA is reduced in acute gout. So, it can

be checked after two to three weeks of the attack and can

be diagnosed. The most common method is to check

hyperuricemia. For the chronic kidney disease

myeloproliferative disorders, it is necessary that they

should be diagnosed by seeing liver function, glucose

level, lipid profile, proper renal function as well as the

full blood count.[25]

Synovial fluid

By using synovial fluid of affected joint and by the

proper examination of the aspirated synovial fluid

through plain light microscopy as well as with the help

of polarized light microscopy, it is found that this fluid is

turbid having low viscosity. For the diagnosis of septic

arthritis we can also perform Gram stain procedure as

well as culturing aspirated synovial fluid. We can also

perform leukocyte counts of the synovial fluid which

may be >10,000/mm.[26]

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Urinary uric acid excretion

xanthine oxidase inhibitors (XOIs) are dangerous in

treating gout and should be checked in patients having

premature onset of gout i.e. before the age of 25 years.

So, this method of diagnosing gout is rarely performed.

24-hour urine collection is usually done for analyzing

uric acid creatinine ratio.[27][28]

CLINICAL METHOD AND IMAGING

Radiography

This method of diagnosing gout is helpful in later stages

of gout. The latest study is carried out for radiographic

damage index of chronic gout. It is such an amazing

scoring system which that is necessary for determination

of the impact of lowering of urates on radiographic

damage. This method also helps in guiding the therapy of

patients having chronic gout. This method of diagnosis is

very feasible and reproducible.[29]

These damage indexes

also associate with the functional capacity. A comparison

of radiography with computed tomography is used for

the assessment of gouty erosions.it is found that

assessment of joints for erosion by using plain

radiography technique is less reliable because of its

small size and due to some degenerative joint disease.[30]

(Fig 9).

Figure 9: Radiographic findings in Gout

Ultrasound

Ultrasound has very high resolution which helps us to

diagnose gout and find out early diagnosis, taking a

therapeutic decision and treating the gout. This method

also helps to assess the extent of lesions and its

therapeutic response. By comparing sonography with X-

ray, we find ultrasonography is more sensitive, non-

invasive, can differentiate between cystic and solid

lesions.[31][32]

It also helps in guidance of biopsies as well

as punctures it is relatively low cost method of diagnosis.

It is useful as it does not use ionizing radiations. It can

detect early changes that take place in soft tissues. This

method is easy to repeat and can be used of dynamic

assessment of the tendons as well as joints. [33][34]

(Fig

10).

Figure 10: Ultrasound analysis of gout affected bone compared to the normal bone as control

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Computed Tomography (CT)

This technique is more sensitive than X-ray and MRI. It

is basically used for identification of bone erosion. The

presence of tophi in intra-articular areas as well as in the

subcutaneous tissues can be diagnosed by computed

tomography. It helps in differentiation of different types

of soft tissue nodules and used to evaluate the damage

that occur in the deeper structures like spine which are

usually not detected by using other methods that do not

use ionizing radiation. The limitation of this method is

that this method is not recommended for diagnosis of

gout on surface structures as it involves ionizing

radiation exposure.[35]

(Fig 11).

Figure 11: Computed Tomographic analysis

(A= Evident gout in fingers on clinical examination

B= Computed tomography showing the 3D volume of affected region

C= Dual energy computed tomography of showing severity in joints)

Dual-energy computed tomography (DECT)

Basically this method is used for differentiating MSU

crystals from that of gout and bone calcification. This

technique is useful to confirm gout in patients having

normal level of uric acid, excluding the disease in the

patients which have hyperuricemia. DECT provides

knowledge of chemical composition of tissues and help

in their differentiation. This technique is size limited

usually of 2 mm so we are not able to detect deposits of

size below this. This method is susceptible to artifacts in

thickened skin areas e.g. heel as well as nails. Its

diagnostic efficiency is low i.e. 50 percent. Its role is

limited due to high cost and due to ionizing radiation

exposure to patient.[35]

Magnetic Resonance Imaging (MRI)

This method is used for differential diagnosis of the

masses of soft tissues. It can detect early stage of

articular erosions which are not detected by

radiography.it can be used to find out actual cause of

painful disorders that changes structure of bones. It is

however, not a routine diagnostic method for tophaceous

gout. By this method, tophi appearance seems to be

variable.it gives morphology of tophi. This method is not

favorable for early gout diagnosis.[36]

(Fig. 12).

Figure 12: Magnetic resonance imaging of gout affected foot

(A and C showing X ray imaging while B and D showing the affected points)

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Treatments and drugs

Gout is mainly treated with drugs like colchicine which

is in fact pain killer for gout. Its low dose is prescribed

for acute gout. Non-steroidal anti-inflammatory drugs

(NSAIDs) include ibuprofen (Advil, Motrin IB) and

naproxen sodium (Aleve, others), as well as

indomethacin and celecoxib (Celebrex) which are very

powerful.[37]

Corticosteroids are also recommended for

patients that are not able to take NSAIDs. They control

pain and inflammation of gout. Corticosteroids are

usually injected in joints. Side effects of these drugs may

include high blood pressure, elevation of blood sugar and

may include change in mood. Xanthine oxidase

inhibitors include allopurinol (Aloprim, Zyloprim) as

well as febuxostat (Uloric) are some of the important

drugs that inhibit and block uric acid production by the

body, hence, reducing risk of gout. Another drug that

lowers the level of uric acid reducing risk of gout, while

increasing level of uric acid in urine is Probenecid.[38][39]

(Table 4)

TABLE 4: Gout’s treatment drugs, cautions associated to them and the particular effect they cause

Treatment drugs Associated cautions Related affects

1. NSAIDs

Indomethacin 50 mg tid (4-10 days)

Naproxen 500 mg bid (4-10 days)

Sulindac 200 mg bid (4-10 days)

Elderly patients, renal insufficiency,

heart failure, peptic ulcer, liver disease,

and concurrent anticoagulants (interacts

with warfarin)

All NSAIDs are effective

2. Corticosterols

Prednisone 20-40 mg daily (2-3 days;

taper over 10-14 days)

Intra-articular methylprednisolone 20-

40 mg dose

Avoid in patients with septic joints; use

with caution in patients with diabetes

Intra-articular therapy is

treatment of choice if 1 or

2 accessible joints are

involved

3. Colchine

0.6 mg orally bid

0.6 mg orally daily or q48h

(depending on renal clearance)

Avoid in severe renal or hepatic

impairment because it can lead to bone

marrow suppression and

neuromyopathy

Use within first 24 hours of

the attack; reduce dosage in

older patients; diarrhea

limits its use

Gout treatment other than drugs include limiting use of

alcohol, limit drinks having fructose, drinking plenty of

water, exercising regularly, weight loss and limiting food

which is rich in purines like sea food, red meat, organ

meat etc.[40][41][42]

Use of coffee also lower uric acid level.

Taking supplements having vitamin C and eating fruits

rich in it like oranges decrease blood uric acid level.

Gout attacks are reduced by eating cherries and taking

drinks having cherry extract. Many other techniques

including relaxation methods like deep-breath exercises

also provide relieve from gout.[43][44][45]

CONCLUSION

Gout is a disease caused by defect in metabolism due to

hyperuricemia. It is actually because of the improper

metabolism of purine, whose breakdown product uric

acid begins to accumulate as the crystals It causes pain in

joint, swelling and redness of bones. Acute gout, chronic

tophaceous gout, transplant associated gout are its types.

Risk factors include drinking alcohol too much and other

genetic factors.it can be diagnosed by using body fluid

like blood, synovial fluid and urine. Imaging methods

include X-ray, MRI, ultrasound, radiography, computed

tomography etc. It is treated by weight loss, taking food

rich in vitamin C and avoiding alcohol. Medication

includes NSAIDS, steroids and colchicine.

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